Human Papillomavirus EQA Programme 2014 (QCMD HPVDNA14)

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Human Papillomavirus EQA

Programme 2014

(QCMD HPVDNA14)

Ed Schuuring

Pathology, UMCG, Groningen, NL Scientific expert and advisor for QCMD HPV Program

Presentatie SKML-deelnemersvergadering

16 juni 2015

Potential conflicts of interest (2011-2015):

member of NVVP-CMDP-HPV-taakgroep

Scientific expert and advisor for QCMD HPV Program (2009-today) Head of HPV-testing lab UMCG/Winschoten/Friesland (cobas HPV test)

Receipt of grants/research support: Hologic, QCMD, CTMM, MDXHealth/OncoMethylome Receipt of honoraria or consultation fees: Hologic, Roche

Speaker’s fee: Hologic, Roche

Travel reimbursements: Hologic, QCMD, Abbott

The early detection of cervical cancer in scraping

population-based screening programs worldwide

1) cytomorphology only The classical approach

2) primary cytomorphology and HPV reflex testing Presently used commonly (eg Dutch guidelines)

3) cytomorphology /HPV co-testing Guideline in USA (Saslow 2012)

4) primary HPV testing and reflex cytomorphology New guideline in NL starting in July 2016; interim guideline in USA 2015

5) primary HPV testing and reflex CINTEC, methylation, hrHPV-typing and others

Presently validated

Normal cervix CIN III

HPV in scrapings of (pre)malignant cervical lesions

~4% high-risk HPV-positive ~85% high-risk HPV-positive

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Praktijkrichtlijn BVO cervixcytologie: indicatie HPV-onderzoek bij Pap2/3A1

Pap 1

97.1% Retour BVO 5 jaar

Pap 2 Pap 3A1 2.1% Herhalen 6 maanden

+ HPV

Pap 1 70% Pap 2 Pap 3A1 25% Pap 3A2> 5% HPV-HPV+ HPV-49% HPV+ 51% Herhalen 12 maanden Gynaecoloog Pap 3A2 > 0,6% Bulkmans, the Lancet, 2007 Bais, Int J Cancer, 2005

Rebolj, Int J Cancer, 2007 J Eijsink

Analytical and clinical sensitivity of HPV-detection assays

Analytical sensitivity of PCR-based methods detecting

<10 HPV copies

Analytical sensitivity of PCR-based methods detecting

<10 HPV copies

Clinical sensitivity of HC2 is 5000 HPV copies

Adapted from Snijders et al. Journal of Pathology 2003; 201:1-6

Clinical validated HPV-tests (in the Netherlands)

Digene HC2 HPV test (Qiagen) GP5+/GP6+ PCR EIA (Vumc/Qiagen) Cobas 4800 HPV test (Roche) Cervista hrHPV test (Hologic)

GenProbe-Aptima hrHPV assay (Hologic) Abbott realtime HR HPV assay (Abbott) Kwantitatieve multiplex RT HPV test (PON)

FDA-approved clinical HPV tests

Digene HC2 HPV test (Qiagen)

Cervista HPV HR test (Hologic) > internal control Cervista HPV 16/18 test (Hologic) > internal control GenProbe-Aptima hrHPV assay (Hologic) > based on RNA

Cobas 4800 HPV test (Roche) > HPV16/18 separate and internal control

Commercial HPV tests • Hybrid Capture 2 Qiagen

• Digene HPV genotyping RH kit Qiagen • Digene HPV genotyping LX kit, Qiagen • Roche Amplicor HPV Test • Roche Linear array HPV Genotyping test • Innogenetics INNO-LiPA HPV Genotyping test • NucliSens EasyQ HPV Biomerieux • Aptima Gen-Probe

• Human Papilloma Virus reagents Third Wave • BIOPAP QTS HPV Kit Loxo

• Reveal HPV Real-Time HPV Detection Kit GenoID • AID STD assay GenID

• AID HPV screening kit GenID • AID HPV typing kit GenID

• Linear ArrayExtra HPV Genotyping Kit Innogenetics • PCR Human Papillomavirus Detection Set Takara Mirus Bio • HPV DNA Chip Biomedlab

• Array Papillomavirus Genomica • ProDect Chip HPV typing Bcs Biotech S.P.A • PapType Genera Biosystems • LCD Array HPV 3.5 Chipron • Seeplex HPV Genotyping Seegene • Viroactiv Virofem

• HPV OncoTest Invirion Diagnostics • Genpoint Tm HPV test Dako-Oxoid • Abbott RealTime High Risk HPV Abbott • Luminex HPV Genotyping, Multimetrix/Progen • Greiner PapilloCheck HPV Screening • PreTect HPV Proofer Norchip • ………

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Andere toepassingen voor HPV testen:

•Follow-up patienten behandeld voor CIN3

•Profylactische vaccinatie

•Therapeutische vaccinitie

•Diagnose RRP (recurrent respiratory papillomatosis)

•Klonale verwantschap

•… …

available HPV EQA platforms

1) QCMD HPVDNA:

• using established cell lines in LBC (~4 HPV types)

2) WHO HPV panel:

• Plasmid DNA spiked into cell line DNA (>30-45 types)

3) NEQAS UK:

• Patient samples (~4 samples) Fagan, JClinVirol2010

ISO17043:2010 accreditated

6th QCMD HPVDNA EQA

Primary goals:

•To assess the proficiency of laboratories in the detection of different high risk Human Papillomavirus (HPV) types

•To provide laboratories with an analytical performance based on the consensus qualitative results of all participants

•To provide feedback on the number and percentage of datasets reporting typing result

Secondary goal:

•To provide laboratories with information on clinical reporting based on the consensus qualitative results of all participants

QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14)

aims

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• Door simulatie van klinische samples mbv “established” BMKH-cellijnen in dunne-laag-cytologie

• Core samples: voor proficiency testing (rapportage performance) • Educational samples: lastige, uitdagende monster ter lering

QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14)

composition EQA panel

_{Human Papillomavirus 2014 EQA Programme}

QCMD – QAV094130 – HPVDNA14

Internationale rondzending:

UMCG: Ed Schuuring (Scientific Advisory Board)

UMCG: Lorian Slagter-Menkema (preparation/validation) UMCG: MD-cytology lab (cobas-HPV testing)

Reference-labs: UMCG and 3 others (?) QCMD: Paul Wallace, Catherina di Lorenze

QCMD = Quality Control for Molecular Diagnostics (Scotland) UMCG = CCKL(ISO15189) accreditated

QCMD 2014 EQA Programme report Nov 2014 QAV094130

QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14) composition EQA panel

•10 samples in PreservCyt

• 4 core samples containing HPV16, 18, 45 or mix 16/18 in BSM using established cell lines • 2 core samples with BSM only as HPV-negative controls

• viral load determined by both cobas and HC2 DNA testing

• 1 education sample with low viral HPV16 load (“clinical HPV-negative”)

• 3 education samples with other HPV genotypes (determined by LIPA) (provided by PON) • all samples pre-tested and confirmed in reference-labs by HC2 (2x) and cobas (2x)

QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14) composition EQA panel

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Primary goals using core samples:

•To provide laboratories with an analytical performance based on the consensus qualitative results of all participants •To provide feedback on the number and percentage of datasets reporting typing result

Secondary goal using educational samples:

•To provide laboratories with information on clinical reporting

based on the consensus qualitative results of all participants QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14)

aims

QCMD 2009/10/11/12/13/14 Human Papillomavirus DNA EQA Programme

participation

HPVDNA09 HPVDNA10 HPVDNA11 HPVDNA12 HPVDNA13 HPVDNA14

Participants 108 155 167 171 194 228 Responders 98 136 149 153 176 203 Countries 26 26 27 31 34 37 Deelnemers in NL 14 21 27 26 31 30 Datasets: - Analytical 113 44 88 91 194 226 - Clinical 113 77 133 144 137 157 - Genotyping 66 84 114 115 136 151

QCMD EQA Programme reports 2009-2014

Qualitive performance of all versus Dutch participants

QCMD-HPVDNA2014 (core samples only)

Performance of all participants Performance of Dutch participants 83.3% 16.7% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0% 6/6 5/6 4/6 3/6 2/6 1/6 0/6 P e rc e n ta g e o f d a ta se ts

Number of core samples correct

Qualitive performance of all versus Dutch participants

QCMD-HPVDNA2014

Performance of all participants

Performance of Dutch participants

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Qualitive performance of all versus Dutch participants

QCMD-HPVDNA2014

Qualitive performance of all versus Dutch participants

QCMD-HPVDNA2014

Qualitive performance of Dutch participants

QCMD-HPVDNA2014

Primary goals using core samples:

•To provide laboratories with an analytical performance based on the consensus qualitative results of all participants •To provide feedback on the number and percentage of datasets reporting typing result

Secondary goal using educational samples:

•To provide laboratories with information on clinical reporting

based on the consensus qualitative results of all participants QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14)

aims

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QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14) composition EQA panel – educational cases

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QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14) composition EQA panel (clinical reporting)

In 2014 clinical performance is NOT reported individually: •QCMD-report provides clinical reporting data separately

•Samples HPV14-10 is considered clinically HPV-negative •For own interpretation only (educational case)

•Sample does NOT represent determination of real clinical outcome •“Impossible” to prepare a clinical relevant sample (HPV-low-copy)

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Clinical reporting of all versus Dutch participants

QCMD-HPVDNA2014

Rapportage van lab dat clinical testing uitvoert

performance-score gebaseerd op core samples

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Rapportage van lab dat clinical testing uitvoert

performance-score

QCMD 2014 Human Papillomavirus DNA EQA Programme (HPVDNA14) composition EQA panel (clinical reporting)

*

Clinical HPV-tests:

HC2: 1 pg/ml = ~5000 kopieën Abbott: = ~5000 kopieën

Cobas = ~300 kopieën (afhankelijk van HPV-type) Pre-test threshold van klinisch-relevante HPV assays

Dus eigenlijk kunnen we geen panel definiëren met een klinische threshold omdat HC2 niet meer de standaard is

Qualitive performance of all versus Dutch participants

QCMD-HPVDNA2014 (core samples only)

83.3% 16.7% 0.0% 0.0% 0.0% 0.0% 0.0% 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 70.0% 80.0% 90.0% 100.0% 6/6 5/6 4/6 3/6 2/6 1/6 0/6 P e rc e n ta g e o f d a ta se ts

Number of core samples correct

2014 2013 2012 NL all all all NL NL

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Vanaf 2013 alleen toetsing performance van analytische interpretatie

Educatief samples alleen als aparte reportage (eigen interpretatie op basis van performance van andere met vergelijkbare testen)

Vanaf 2015 tabel bij individual reporting cores en educational samples apart Kleinere panels en meer rondzendingen/jaar (>2016)

Andere matrices (nu een pilot SurePath)

Ontwikkelen van referentie/calibratie-sets (pilot 2015) QCMD HPV testen vanaf 2015 (planning)

Human Papillomavirus EQA Programme 2014 (QCMD HPVDNA14)